Overview of Promotion as a Mechanism in Carcinogenesis

Abstract

Considerable evidence has accumulated that cancer is a multifactorial and multistep process. Cancer does not result from a simple exposure to a single exogenous factor but rather from a complex interaction between exogenous and/or endogenous factors. The model of chemical carcinogenesis in mouse skin designed by Berenblum (1) and Mottram (2) has led to the characterization of two stages in carcinogenesis, initiation and promotion, caused by two different classes of agents, the initiators and the promoters. More recently, models of cultured cells have provided evidence that cell transformation by chemical carcinogens, U.V. light or X-rays, requires at least two steps. As a result of probability-based studies J. Little and co-workers have emphasized that the initial step is a frequent event since 100 % of the progeny of methylcholanthrene-treated cells are potentially transformed or “initiated” cells. However, a very small minority of the progeny of initiated cells actually yields transformed colonies, suggesting that a second step occurs which is a very rare event. This second step behaves like a spontaneous mutation in that it has small but constant probability of occurring each time an initiated cell divides (3). The requirement for two genetic events in the process of cancer appears to be in agreement with the results of transfection experiments, which indicate that at least two cooperating oncogenes are needed to convert embryo fibroblasts in primary cultures into tumor cells (4). Likewise, the model of transgenic mice in which oncogenes were expressed from tissue-specific promoters, has allowed to state that the expression of oncogen appears to result in hyperplasia with tumors arising as a rare clonal outgrowth, suggesting also the occurrence of secondary events.